CTFR 16/643,607 CTFR 81964 DETAILED ACTION 07-03-aia AIA 15-10-aia The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA. Claims 1, 8-11, 14-16 and 18-20 are pending. Claims 14-16 and 18-20 have been withdrawn. Claims 1 and 8-11 are currently under examination. 35 USC § 103 rejections maintained The rejections of claims 1 and 8-11 under 35 U.S.C. 103(a) as being unpatentable over Won et al (WO 2016/112314, published July 14, 2016, IDS) in view of Werner et al. ( Int. J. Radiat. Oncol. Biol. Phys. 2013 Jul 1; 86 (3): 463-468, cited previously) in further view of Moore et al Mol Pharm 11:24-39, 2014) and Kaittanis et al Crit Rev Oncogenesis 19:143-176, 2014) are maintained. The claims are drawn to a composition comprising one or more CaWO4 (CWO) nanoparticles; and a chemotherapeutic drug co-encapsulated in a capsule consisting of PEG-PLA block copolymer (BCP). Won discloses CaWO4 (CWO) nanoparticles in a capsule consisting of PEG-PLA block copolymer with a mean diameter between 1 and 500 nm for use in in vivo biomedical imaging. (paragraphs 7, 34, 44, 46, 48-50; Abstract). Won does not disclose a chemotherapeutic drug co-encapsulated in the capsule. Werner disclose that nanoparticle chemotherapeutics can be used advantageously due to their preferential accumulation in tumors and teaches GENEXOL-PM, a polymeric nanoparticle formulation of paclitaxel in which a biocompatible block polymer encapsulates the chemotherapeutic agent; (Abstract; pages 2, 2 nd paragraph ). One of ordinary skill in the art would have been motivated to apply Werner’s formulation comprising paclitaxel to Won’s CaWO4 (CWO) nanoparticles in a capsule consisting of PEG-PLA block copolymer because both Moore and Kaittanis discuss the advantages of nanoparticles with particles for imaging purposes along with a therapeutic agent. Moore discloses that theranostic nanomedicines, systems that combine therapeutic and diagnostic modalities into a single package, which are able to provide real-time information of a drug delivery system’s biodistribution, drug concentration, or drug release kinetics (page 25, 1 st column, 3 rd paragraph; Figure 1). Moore disclose nanoparticles comprising paclitaxel (Figure 9). Moore discloses that radioluminescence particles are activated by X-ray radiation (page 30). Kaittanis disclose nanoparticles comprising both imaging agents as well as therapeutic agents (page 143; Fig. 1). Kaittanis disclose metal-based nanoparticles for imaging (Fig. 2). Kaittanis disclose nanoparticles comprising modified poly(aspartic acid) linked to PEG for delivery of paclitaxel (page 153, 2 nd column). Thus, absent unexpected results it would have been prima facie obvious to enclose Werner’s formulation comprising paclitaxel to Won’s capsule consisting of PEG-PLA block copolymer comprising CaWO4 (CWO) nanoparticles to have a composition comprising one or more CaWO4 (CWO) nanoparticles and a chemotherapeutic drug co-encapsulated in a capsule consisting of PEG-PLA block copolymer (BCP). The limitation “upon receiving a dose of X-ray radiation, the one or more CWO nanoparticles emit UV-A, causing photolytic degradation of the capsule and release of the chemotherapeutic drug from the inside of the capsule to the outside of the capsule” has been interpreted as being a function of the composition comprising one or more CaWO4 (CWO) nanoparticles; and a chemotherapeutic drug co-encapsulated in a capsule consisting of PEG-PLA block copolymer. The claims read on the product per se , the composition comprising one or more CaWO4 (CWO) nanoparticles; and a chemotherapeutic drug co-encapsulated in a capsule consisting of PEG-PLA block copolymer. Therefore, since the prior art teaches the identical structure, the properties applicant discloses and/or claims are necessarily present. In re Spada, 911 F.2d 705, 709, 15 USPQ2d 1655, 1658 (Fed. Cir. 1990). See MPEP 2112.01. While neither Won nor Werner explicitly disclose the function of the composition comprising one or more CaWO4 (CWO) nanoparticles and a chemotherapeutic drug co-encapsulated in a capsule consisting of PEG-PLA block copolymer, the composition is identical to the claimed composition and thus the composition comprising one or more CaWO4 (CWO) nanoparticles and a chemotherapeutic drug co-encapsulated in a capsule consisting of PEG-PLA block copolymer disclosed by Won and Werner would inherently possess the ability of upon receiving a dose of X-ray radiation, the one or more CWO nanoparticles emit UV-A, causing photolytic degradation of the capsule and release of the chemotherapeutic drug from the inside of the capsule to the outside of the capsule The wherein clause does not recite any additional elements to the composition but simply states a characterization of the composition. In response to Applicant’s argument that even though those features are not structural, they are features that should be given patentable weight as they stem directly from the structural features recited before the "wherein" clause MPEP 2173.05(g), MPEP §2173.05 recites A functional limitation must be evaluated and considered, just like any other limitation of the claim, for what it fairly conveys to a person of ordinary skill in the pertinent art in the context in which it is used. A functional limitation is often used in association with an element, ingredient, or step of a process to define a particular capability or purpose that is served by the recited element, ingredient or step. In Innova/Pure Water Inc. v. Safari Water Filtration Sys. Inc., 381 F.3d 1111, 1117-20, 72 USPQ2d 1001, 1006-08 (Fed. Cir. 2004), the court noted that the claim term "operatively connected" is "a general descriptive claim term frequently used in patent drafting to reflect a functional relationship between claimed components," that is, the term "means the claimed components must be connected in a way to perform a designated function." "In the absence of modifiers, general descriptive terms are typically construed as having their full meaning." Id. at 1118, 72 USPQ2d at 1006. In the patent claim at issue, "subject to any clear and unmistakable disavowal of claim scope, the term ‘operatively connected’ takes the full breath of its ordinary meaning, i.e., ‘said tube [is] operatively connected to said cap’ when the tube and cap are arranged in a manner capable of performing the function of filtering." Id. at 1120, 72 USPQ2d at 1008. As discussed previously, all the structural features of the composition are known in the art. Thus, the functional features recited in the claims stem directly from the structural features disclosed in the art. Applicant argues that the term "co-encapsulated" is itself a structural feature dictating that both components reside within the same encapsulating structure. This is distinct from a formulation where imaging particles and drug particles exist as separate populations, each in their own capsules. Applicant argues that the cited art, at best, only describes the latter scenario through the proposed combination of Won (CWO-in-capsules) plus Werner (drug-in-capsules). Applicant argue that the experimental results confirm Applicant's interpretation------only when CWO and PTX are in the same capsule does the suppressed baseline release and triggered burst release occur. Applicant argues that a mixture of separate CWO-only and PIX-only particles would not exhibit these properties. Applicant states that the Patent Office asserts that Won discloses CWO nanoparticles encapsulated in PEG-PLA and admits that that Won "does not disclose a chemotherapeutic drug co-encapsulated in the capsule." Applicant argues the Patent Office relies on Werner's disclosure of GENEXOL-PM, which is a PEG-PLA micellar composition encapsulating paclitaxel. Applicant argues that the Patent Office's thesis is that"[ o ]ne of ordinary skill in the art would have been motivated to apply Werner's formulation comprising paclitaxel to Won's CaWO4 (CWO) nanoparticles in a capsule consisting of PEG-PLA block copolymer because both Moore and Kaittanis discuss the advantages of nanoparticles with particles for imaging purposes along with a therapeutic agent." Applicant argues that even if all that were true, and Applicant is not admitting as much, there are numerous reasons why there is no motivation in any of the cited references, even when combined, to place CWO within the same capsule as a chemotherapeutic agent with the reasonable expectation of releasing the chemotherapeutic agent from the claimed structure upon the application of a dose of X-ray radiation. Applicant argues that it is worth pointing out that the fact that Won teaches CWO in PEG-PLA does not make it obvious to add a chemotherapeutic drug especially given that Won's entire focus is on imaging and radio-sensitization-there is no suggestion, teaching, or motivation to add therapeutic cargo. In addition, Applicant argues that although Won describes the emission of UV-AJblue light radiation from CWO under X-ray irradiation, Won does not teach or suggest that this UV emission could or would degrade PEGPLA or trigger drug release. Applicant argues that even if PLA photodegradation by UV light were generally known and Applicant is not admitting as much------the cited art does not teach using X-ray-triggered CWO radioluminescence to intentionally degrade a drug-loaded PEG-PLA capsule for triggered release. Applicant’s arguments have been considered but are not persuasive. In response to applicant's arguments against the Won, Werner, Moore and Kaittanis individually, one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller , 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986). Won discloses CaWO4 (CWO) nanoparticles in a capsule consisting of PEG-PLA block copolymer. Won disclose that CWO NPs were encapsulated in biocompatible BCPs such as PEG-PnBA or PEG-PLA (paragraph 49). Won disclose that the BCP coating structure does not influence the luminescence properties of CWO NPs (paragraph 48). Won discloses a formulation comprising a crystalline metal tungstate particle and/or particle aggregate encapsulated within a biocompatible polymeric coating material (paragraph 44). Won discloses that the coating material includes polyethylene glycol (PEG), poly(D,L-lactic acid) (PLA), poly(D,L-lactic acid-ran-glycolic acid) (PLGA), poly(E- 15 caprolactone) (PCL), poly(styrene) (PS), poly(n-butyl acrylate) (PnBA), and/or any copolymeric combination of two or more of these polymer components (paragraph 45). Werner teaches GENEXOL-PM, a polymeric nanoparticle formulation of paclitaxel in which a biocompatible block polymer encapsulates the chemotherapeutic agent. Both Moore (Figures 6-8) and Kaittanis (Fig 1) disclose chemotherapeutic agents co-encapsulated with a magnetic label. Moore discloses radioluminescent Gd2O2S nanoparticles were coated layer by layer with poly(styrenesulfonate sodium) (PSS) and poly(allyl-amine HCl) (PAH). Won discloses formulation comprising a crystalline metal tungstate particle or particle aggregate encapsulated within a biocompatible polymeric coating material (paragraph 7). Thus, it would have been obvious to combine Werner’s biocompatible block polymer encapsulates the chemotherapeutic agent comprising paclitaxel with Won’s CaWO4 (CWO) nanoparticles in a capsule consisting of PEG-PLA block copolymer because both Moore and Kaittanis discuss the advantages of nanoparticles with particles for imaging purposes along with a therapeutic agent. Moore discloses that theranostic nanomedicines, systems that combine therapeutic and diagnostic modalities into a single package, which are able to provide real-time information of a drug delivery system’s biodistribution, drug concentration, or drug release kinetics. In response to Applicant’s argument that there are numerous reasons why there is no motivation in any of the cited references, even when combined, to place CWO within the same capsule as a chemotherapeutic agent with the reasonable expectation of releasing the chemotherapeutic agent from the claimed structure upon the application of a dose of xray radiation, both Moore and Kaittanis discuss the advantages of nanoparticles with particles for imaging purposes along with a therapeutic agent In response to Applicant’s argument that Won does not teach or suggest that this UV emission could or would degrade PEGPLA or trigger drug release, this would be an inherent property of a CaWO4 (CWO) nanoparticles encapsulated within a capsule consisting of PEG-PLA block-copolymer (BCP). In addition, Applicant argues unexpected results. Applicant argues that the surprising, unexpected, and significant experimental results from the 32-day study described in the instant application militate against a holding of obviousness. Applicant argues that these results demonstrate a surprising, unexpected, and dramatic/significant ~61 % difference in the effect of x-rays when CWO is co-encapsulated with PTX. Applicant argues that co-encapsulation with CWO dramatically reduces spontaneous drug release (29% vs. 74% over 32 days). Applicant argues that this suggests PTX has strong affinity for CaWO4. Applicant argues that X-ray triggering only works with CWO: The PEG-PLA/PTX system showed minimal response to X-ray radiation, while PEG-PLA/CWO/PTX showed dramatic burst release upon irradiation. Applicant argues that the CWO system provides both: (a) storage stability when no radiation is present, and on-demand release when radiation is applied, creating a true "controlled release" system. Applicant argues that these results demonstrate that only the co-encapsulated structure (where C\VO and PTX are together in the same capsule) can achieve the wherein clause's functional result-X-ray triggered UV-A emission causing photolytic degradation and drug release. Applicant argues that skilled people with the cited references before them would not have expected any of these surprising, unexpected, and significant results. Applicant argues that those of skill in the art would not have expected that there would be an affinity between PTX and CWO that would lead to suppression of PTX baseline release or that release would only be triggered when the PTX and the CWO were both inside the same capsule as claimed. Applicant argues that these data strongly support Applicant's position that the cited art structures (separate CWO-only and PTX-only capsules) cannot achieve the claimed functional result. Applicant argues that the wherein clause specifies: "upon receiving a dose of X-ray radiation, the one or more CWO nanoparticles emit UV-A, causing photolytic degradation of the capsule and release of the chemotherapeutic drug from the inside of the capsule to the outside of the capsule." Applicant argues that this functional feature underscores the beneficial nature of the co-encapsulation arrangement: 1. The CWO nanoparticles are positioned within the capsule and emit UV-A that causes photolytic degradation of that specific capsule structure; 2. The chemotherapeutic drug is inside that same capsule and is presumably in contact with the C\VO so it can be released only when that capsule degrades; and 3. This mechanism cannot function with separate capsules------Werner's drug-only capsules lack the CWO nanoparticles needed to generate the UV-A emission and would indeed release drug much more quickly without application of x-rays. Applicant argues that the experimental data prove that the wherein clause is not inherent to any structure with CWO and drug------the PEG-PLA/PTX system (drug without CWO) showed minimal X-ray response (7% difference). Applicant argues that only the co-encapsulated structure enables the 61% X-ray-triggered release effect. In addition, Applicant argues that Won explicitly teaches CWO nanoparticles encapsulated in PEG-PLA "for use in in vivo biomedical imaging" Applicant argue Won's formulations contain only CWO nanoparticles within the polymer capsule-no therapeutic agent is present. Applicant argues that Won's entire disclosure focuses on imaging and radiosensitization applications, stating the formulations "render metal tungstate or metal molybdate particles suitable for in vivo biomedical imaging and therapeutic applications" through radioluminescence properties. Applicant argues that Won does not suggest placing a chemotherapeutic drug molecule inside the same capsule with the CWO nanoparticles. Applicant argues that the inventors of the claimed invention were the first to (i) think of placing CWO nanoparticles in the same capsule as a hemotherapeutic drug"; and (ii) consider that application of a dose of x-ray radiation to a capsule comprising CWO and a chemotherapeutic agent might release the chemotherapeutic agent Applicant argues that Moore and Kaittanis do not suggest and would not motivate the co-encapsulation of CWO nanoparticles together with a chemotherapeutic drug in a PEG-PLA capsule. Moore describes multiple theranostic platforms including: porous silicon with drug in pores (Figure 2), pH-sensitive micelles with drug in hydrophobic core (Figure 3), quantum dots with surface-bound drug (Figure 4), and mesoporous shells around cores (Figure 5). Applicant argues that in each system, the imaging and drug components occupy distinct spatial domains-not co-encapsulated together in a single compartment. Applicant further argues Kaittanis discusses various theranostic platforms including polymer-drug conjugates, liposomes with separate imaging/drug components, and surface-modified nanoparticles. Applicant argues that neither Moore nor Kaittanis teach co-encapsulating imaging nanoparticles with drugs in the same polymer capsule core. Applicant argues that Moore and Kaittanis appear to teach the opposite, to keep things separate. Applicant’s arguments have been considered but are not persuasive. It is noted that the claims are drawn to a composition comprising CWO co-encapsulated with a chemotherapeutic drug in a capsule consisting of PEG-PLA block-copolymer, not a method of using the radiation-triggered controlled release drug composition for treating patients. As previously disclosed the limitation “wherein upon receiving a dose of X-ray radiation, the one or more CWO nanoparticles emit UV-A, causing photolytic degradation of the capsule and release of the chemotherapeutic drug from the inside of the capsule to the outside of the capsule states a characterization of the composition. As discussed previously, both Moore (Figure 6) and Kaittanis (Fig 1) disclose chemotherapeutic agents co-encapsulated with a radio-luminescent nanoparticle for use in cancer imaging and therapy. Both Moore and Kaittanis disclose the irradiation of the encapsulated chemotherapeutic agents and radio-luminescent nanoparticles with X-Rays. Won discloses CaWO4 (CWO) nanoparticles in a capsule consisting of PEG-PLA block copolymer. Werner teaches a polymeric nanoparticle formulation of paclitaxel in which a biocompatible block polymer encapsulates the chemotherapeutic agent. Thus, it would have been obvious to make a composition comprising a CaWO4 nanoparticle co-encapsulated with a chemotherapeutic in a capsule consisting of PEG-PLA block-copolymer. The question is whether the specific composition exhibit unexpected results. As discussed previously, the claims are drawn to a composition, not a method of using the composition. Both the claimed composition and the composition of radio-luminescent nanoparticles and chemotherapeutic agent envisioned by Moore and Kaittanis are treating cancer and irradiated with X-rays. Thus, the unexpected results claimed by Applicant would likely be an inherent property of the radio-luminescent nanoparticles and chemotherapeutic agent encapsulated in a lipid capsule, unless the CWO nanoparticles exhibited different properties compared to the radio-luminescent nanoparticles of Moore and Kaittanis. The specification disclose that the PTX release rate is controlled by radiation dose (paragraph 17). This concept may be applied to any other combination of choices for radio-luminescent nanoparticles. Applicant has not demonstrated that the CWO nanoparticles exhibited different properties compared to other radio-luminescent nanoparticles In addition, the specification appears to disclose that PTX is encapsulated within the hydrophobic PLA layer. It is well known that paclitaxel is a highly hydrophobic compound. Thus, it is not likely that any chemotherapeutic would function as PTX. MPEP 716.02(d) states Whether the unexpected results are the result of unexpectedly improved results or a property not taught by the prior art, the “objective evidence of nonobviousness must be commensurate in scope with the claims which the evidence is offered to support.” In other words, the showing of unexpected results must be reviewed to see if the results occur over the entire claimed range. In re Clemens, 622 F.2d 1029, 1036, 206 USPQ 289, 296 (CCPA 1980) (Claims were directed to a process for removing corrosion at “elevated temperatures” using a certain ion exchange resin (with the exception of claim 8 which recited a temperature in excess of 100 C ). Appellant demonstrated unexpected results via comparative tests with the prior art ion exchange resin at 110C and 130C. The court affirmed the rejection of claims 1-7 and 9-10 because the term “elevated temperatures” encompassed temperatures as low as 60C where the prior art ion exchange resin was known to perform well. The rejection of claim 8, directed to a temperature in excess of 100C, was reversed.). See also In re Peterson, 315 F.3d 1325, 1329-31, 65 USPQ2d 1379, 1382-85 (Fed. Cir. 2003) (data showing improved alloy strength with the addition of 2% rhenium did not evidence unexpected results for the entire claimed range of about 1-3% rhenium); In re Grasselli, 713 F.2d 731, 741, 218 USPQ 769, 777 (Fed. Cir. 1983) (Claims were directed to certain catalysts containing an alkali metal. Evidence presented to rebut an obviousness rejection compared catalysts containing sodium with the prior art. The court held this evidence insufficient to rebut the prima facie case because experiments limited to sodium were not commensurate in scope with the claims.). In response to Applicant argument that Moore and Kaittanis appear to teach the opposite, to keep things separate, both Moore and Kaittanis disclose examples of radiotherapeutic agents and chemotherapeutic agents within the same compartment within a lipid capsule. It is noted that a prior art reference is relevant for all its teachings, not only its examples. Merck & Co. v. Biocraft Labs., Inc., 874 F.2d 804, 807 (Fed. Cir. 1989) (holding that both preferred and unpreferred embodiments must be considered). In addition, Art is art, not only for what it expressly teaches, but also for what it would reasonably suggest to the skilled artisan, including alternative or non-preferred embodiments. MPEP § 2123. Furthermore, the specification discloses that the CWO NP core is coated with hydrophobic PLA chains. PTX is encapsulated within the hydrophobic PLA layer (paragraph 17). The specification discloses that under X-ray irradiation, UV-A is generated by CWO NPs, and the X-ray/UV-A causes the release of PTX from the PLA layer into the aqueous surrounding (Id). So it does appear that CWO NPs and PTX are not completely intermingled within the PEG-PLA block-copolymer. In response to Applicant’s argument that those of skill in the art would not have expected that there would be an affinity between PTX and CWO that would lead to suppression of PTX baseline release or that release would only be triggered when the PTX and the CWO were both inside the same capsule as claimed, it appears from the specification that the PTX and CWO were not intermingled. The specification appears to disclose that PTX is encapsulated within the hydrophobic PLA layer. It does not appear likely that the highly hydrophobic paclitaxel would have an affinity for CWO. Summary Claims 1 and 8-11 stand rejected 07-39 AIA THIS ACTION IS MADE FINAL. Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a). A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action. Any inquiry concerning this communication or earlier communications from the examiner should be directed to Mark Halvorson whose telephone number is (571) 272-6539. The examiner can normally be reached on Monday through Friday from 9:00 am to 6:00 pm. If attempts to reach the examiner by telephone are unsuccessful, the examiner's supervisor, Gregory Emch, can be reached at (571) 272-8149. The fax phone number for this Art Unit is (571) 273-8300. Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice. Information regarding the status of an application may be obtained from the Patent Application Information Retrieval (PAIR) system. Status information for published applications may be obtained from either Private PAIR or Public PAIR. Status information for unpublished applications is available through Private PAIR only. For more information about the PAIR system, see http://pair-direct.uspto.gov. Should you have questions on access to the Private PAIR system, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative or access to the automated information system, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000. /MARK HALVORSON/Primary Examiner, Art Unit 1646 Application/Control Number: 16/643,607 Page 2 Art Unit: 1646 Application/Control Number: 16/643,607 Page 3 Art Unit: 1646 Application/Control Number: 16/643,607 Page 4 Art Unit: 1646
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